Cell based dATP delivery as a therapy for chronic heart failure
Abstract Transplanted human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) improve ventricular performance when delivered acutely post-myocardial infarction but are ineffective in chronic myocardial infarction/heart failure. 2’-deoxy-ATP (dATP) activates cardiac myosin and potently increases contractility. Here we engineered hPSC-CMs to overexpress ribonucleotide reductase, the enzyme controlling dATP production. In vivo, dATP-producing CMs formed new myocardium that transferred dATP to host cardiomyocytes via gap junctions, increasing their dATP levels. Strikingly, when transplanted into chronically infarcted hearts, dATP-producing grafts increased left ventricular function, whereas heart failure worsened with wild-type grafts or vehicle injections. dATP-donor cells recipients had greater voluntary exercise, improved cardiac metabolism, reduced pulmonary congestion and pathological cardiac hypertrophy, and improved survival. This combination of remuscularization plus enhanced host contractility offers a novel approach to treating the chronically failing heart.One Sentence Summary Transplanting gene-edited dATP-donor cardiomyocytes in chronically infarcted heart restores their cardiac function, improving both exercise tolerance and survival..
Medienart: |
Preprint |
---|
Erscheinungsjahr: |
2023 |
---|---|
Erschienen: |
2023 |
Enthalten in: |
bioRxiv.org - (2023) vom: 02. Mai Zur Gesamtaufnahme - year:2023 |
---|
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Mhatre, Ketaki N [VerfasserIn] |
---|
Links: |
Volltext [kostenfrei] |
---|
Themen: |
---|
doi: |
10.1101/2023.04.24.538108 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
XBI039398307 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | XBI039398307 | ||
003 | DE-627 | ||
005 | 20231205145236.0 | ||
007 | cr uuu---uuuuu | ||
008 | 230429s2023 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1101/2023.04.24.538108 |2 doi | |
035 | |a (DE-627)XBI039398307 | ||
035 | |a (biorXiv)10.1101/2023.04.24.538108 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Mhatre, Ketaki N |e verfasserin |4 aut | |
245 | 1 | 0 | |a Cell based dATP delivery as a therapy for chronic heart failure |
264 | 1 | |c 2023 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a Computermedien |b c |2 rdamedia | ||
338 | |a Online-Ressource |b cr |2 rdacarrier | ||
520 | |a Abstract Transplanted human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) improve ventricular performance when delivered acutely post-myocardial infarction but are ineffective in chronic myocardial infarction/heart failure. 2’-deoxy-ATP (dATP) activates cardiac myosin and potently increases contractility. Here we engineered hPSC-CMs to overexpress ribonucleotide reductase, the enzyme controlling dATP production. In vivo, dATP-producing CMs formed new myocardium that transferred dATP to host cardiomyocytes via gap junctions, increasing their dATP levels. Strikingly, when transplanted into chronically infarcted hearts, dATP-producing grafts increased left ventricular function, whereas heart failure worsened with wild-type grafts or vehicle injections. dATP-donor cells recipients had greater voluntary exercise, improved cardiac metabolism, reduced pulmonary congestion and pathological cardiac hypertrophy, and improved survival. This combination of remuscularization plus enhanced host contractility offers a novel approach to treating the chronically failing heart.One Sentence Summary Transplanting gene-edited dATP-donor cardiomyocytes in chronically infarcted heart restores their cardiac function, improving both exercise tolerance and survival. | ||
650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
700 | 1 | |a Mathieu, Julie |4 aut | |
700 | 1 | |a Martinson, Amy |4 aut | |
700 | 1 | |a Flint, Galina |4 aut | |
700 | 1 | |a Blakley, Leslie P. |4 aut | |
700 | 1 | |a Tabesh, Arash |4 aut | |
700 | 1 | |a Reinecke, Hans |4 aut | |
700 | 1 | |a Yang, Xiulan |4 aut | |
700 | 1 | |a Guan, Xuan |4 aut | |
700 | 1 | |a Murali, Eesha |4 aut | |
700 | 1 | |a Klaiman, Jordan M |4 aut | |
700 | 1 | |a Odom, Guy L |4 aut | |
700 | 1 | |a Brown, Mary Beth |4 aut | |
700 | 1 | |a Tian, Rong |4 aut | |
700 | 1 | |a Hauschka, Stephen D |4 aut | |
700 | 1 | |a Raftery, Daniel |4 aut | |
700 | 1 | |a Moussavi-Harami, Farid |0 (orcid)0000-0002-0189-7214 |4 aut | |
700 | 1 | |a Regnier, Michael |4 aut | |
700 | 1 | |a Murry, Charles E |4 aut | |
773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2023) vom: 02. Mai |
773 | 1 | 8 | |g year:2023 |g day:02 |g month:05 |
856 | 4 | 0 | |u http://dx.doi.org/10.1101/2023.04.24.538108 |z kostenfrei |3 Volltext |
912 | |a GBV_XBI | ||
951 | |a AR | ||
952 | |j 2023 |b 02 |c 05 |